Grapefruit's Bitter Taste Holds a Sweet Promise for Diabetes Therapy

Naringenin, an antioxidant derived from the bitter flavor of grapefruits and other citrus fruits, may cause the liver to break down fat while increasing insulin sensitivity, a process that naturally occurs during long periods of fasting.

A team of researchers from the Hebrew University of Jerusalem and Massachusetts General Hospital (MGH) report that naringenin activates a family of small proteins, called nuclear receptors, causing the liver to break down fatty acids. In fact, the compound seems to mimic the actions of other drugs, such as the lipid-lowering Fenofibrate and the anti-diabetic Rosiglitazone, offering the advantages of both. If the results of this study extend to human patients, this dietary supplement could become a staple in the treatment of hyperlipidemia, type-2 diabetes, and perhaps metabolic syndrome. The report appears in this week issue of the online journal PLoS ONE.

100825174110-large“It is a fascinating find,” says Yaakov Nahmias, PhD, of the Hebrew University of Jerusalem the paper’s senior author. “We show the mechanism by which naringenin increases two important pharmaceutical targets, PPARα and PPARγ, while blocking a third, LXRα. The results are similar to those induced by long periods of fasting.”

The liver is the main organ responsible for the regulation of carbohydrate and lipid levels in the blood. Following a meal, the blood is flushed with sugars, which activate LXRα, causing the liver to create fatty acids for long-term storage. During fasting, the process is reversed; fatty acids are released by fat cells, activate PPARα in the liver, and are broken down to ketones. A similar process, involving PPARγ, increases sensitivity to insulin.

“It is a process which is similar to the Atkins diet, without many of the side effects,” says Martin L. Yarmush, MD, PhD, director of the MGH Center for Engineering in Medicine and one of the paper’s authors.

“The liver behaves as if fasting, breaking down fatty acids instead of carbohydrates.” Yarmush is the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School.

“Dual PPARα and PPARγ agonists, like naringenin, were long sought after by the pharmaceutical industry,” says Nahmias, “but their development was plagued by safety concerns. Remarkably, naringenin is a dietary supplement with a clear safety record. Evidence suggests it might actually protect the liver from damage.”

Grapefruit’s bitter taste is caused the presence of the flavonoid naringin, which is broken down in the gut into naringenin. Earlier evidence has shown the compound has cholesterol lowering properties and may ameliorate some of the symptoms associated with diabetes. The researchers demonstrated that the compound activates PPARα and PPARγ by dramatically increasing the levels of a co-activator peptide of both, called PGC1α. At the same time, naringenin bound directly to LXRα, blocking its activation. These effects culminated with increased fatty acid oxidation and the inhibition of vLDL (‘bad cholesterol’) production.

Additional co-authors of the PLoS ONE paper are Jonathan Goldwasser, PhD, Eric Yang, PhD, MGH; Pazit Cohen, PhD, Hebrew University; and Patrick Balaguer, PhD, INSERM Univ. Montpellier France. The work was supported by grants from the National Institutes of Health (NIH) and European Research Council (ERC).

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K01DK080241), a European Research Council starting grant (TMIHCV 242699), and the Harvard Clinical Nutrition Research Center (P30-DK040561). Resources were provided by the BioMEMS Resource Center (P41 EB-002503), Shriners Burns Hospital, and the Alexander Silberman Institute of Life Sciences.

ScienceDaily (Aug. 25, 2010)

Green Tea Extract Appears to Keep Cancer in Check in Majority of CLL Patients

An extract of green tea appears to have clinical activity with low toxicity in chronic lymphocytic leukemia (CLL) patients who used it in a phase II clinical trial, say researchers at Mayo Clinic.

The findings were presented June 7 during the annual meeting of the American Society of Clinical Oncology (ASCO). They are the latest in a series of Mayo studies to show promise for use of the chemical epigallocatechin gallate (EGCG) — the major component of green tea — in reducing the number of leukemia cells in patients with CLL. Mayo first tested EGCG in a variety of laboratory assays about eight years ago, and it was found to reduce the survival of CLL leukemic cells. This laboratory finding was followed by a successful phase I clinical trial — the first time green tea extract had been studied in CLL patients.

“Although only a comparative phase III trial can determine whether EGCG can delay progression of CLL, the benefits we have seen in most CLL patients who use the chemical suggest that it has modest clinical activity and may be useful for stabilizing this form of leukemia, potentially slowing it down,” says Tait Shanafelt, M.D., a Mayo Clinic hematologist and lead author of the study.

“These studies advance the notion that a nutraceutical like EGCG can and should be studied as cancer preventives,” says Neil Kay, M.D., a hematology researcher whose laboratory first tested the green tea extract in leukemic blood cells from CLL patients. “Using nontoxic chemicals to push back cancer growth to delay the need for toxic therapies is a worthy goal in oncology research — particularly for forms of cancer initially managed by observation such as CLL.”

Drs. Shanafelt and Kay caution that EGCG is not a substitute for chemotherapy. All of the patients Mayo tested with EGCG were early stage, asymptomatic CLL patients who would not otherwise be treated until their disease progressed. The extract was supplied by the National Cancer Institute (NCI) and Polyphenon E International for these initial clinical trials.

CLL is a blood cancer that is a hybrid between leukemia and lymphoma. Progression of the disease is measured by the quantity of leukemia cells in the blood and bone marrow as well as enlargement of lymph nodes due to infiltration by the leukemia cells. In the phase I study, published in May 2009 in the Journal of Clinical Oncology, researchers found that the blood lymphocyte (leukemia cell) count was reduced in one-third of participants, and that the majority of patients who entered the study with enlarged lymph nodes due to involvement by CLL saw a 50 percent or greater reduction in their lymph node size.

Using the highest dose tested in the phase I study, the researchers launched their phase II clinical trial in an additional 36 patients. The results presented at the ASCO meeting evaluate the effects in these 36 patients as well as the six patients from the phase I trial treated at the same dose (total 42 patients). Results from 41 patients who have completed the study show that 31 percent of patients had a 20 percent or greater sustained reduction in blood leukemia count, and 69 percent of patients with enlarged lymph nodes saw a reduction of node size of 50 percent or greater.

In all, 69 percent of CLL patients had a biological response to EGCG as evidenced by a 20 percent or greater sustained reduction in blood lymphocyte count and/or a 50 percent or greater reduction in lymph node size, the researchers say.

Because EGCG was being studied in patients who did not otherwise need treatment, the researchers took a rigorous approach toward studying side effects. Most clinical trials of therapeutic agents only report grade 3 and higher side effects, but the researchers looked at and reported grade 1 and grade 2 as well. While a number of patients had transient grade 1 or 2 side effects, only three of 42 experienced a grade 3 side effect during their six months of treatment.

“All in all, the treatment was well tolerated with very mild side effects in most patients,” Dr. Shanafelt says.

The researchers say that the prior publications on the effects of EGCG on CLL leukemia cells in the laboratory and the data from the published phase I study have been widely disseminated via the Internet by patient advocacy groups. Based on information from patients and colleagues throughout the country, the Mayo researchers have become aware that many CLL patients nationwide have started to use EGCG supplements, which are readily available over the counter.

“Without a phase III clinical trial, we cannot make a recommendation that EGCG be used by CLL patients, but those who want to take supplements should consult with their oncologists and need to receive appropriate monitoring using laboratory tests,” Dr. Kay says.

The study was funded by grants from the NCI, the Mayo Comprehensive Cancer Center and from donors and patient advocacy foundations.

ScienceDaily (June 4, 2010)

Biochemist Proposes Worldwide Policy Change to Step Up Daily Vitamin D Intake

Anthony Norman, a leading international expert in vitamin D, proposes worldwide policy changes regarding people’s vitamin D daily intake amount in order to maximize the vitamin’s contribution to reducing the frequency of many diseases, including childhood rickets, adult osteomalacia, cancer, autoimmune type-1 diabetes, hypertension, cardiovascular disease, obesity and muscle weakness.

“A reduction in the frequency of these diseases would increase the quality and longevity of life and significantly reduce the cost of medical care worldwide,” said Norman, a distinguished professor emeritus of biochemistry and biomedical sciences at the University of California, Riverside. “It is high time that worldwide vitamin D nutritional policy, now at a crossroads, reflects current scientific knowledge about the vitamin’s many benefits and develops a sound vision for the future.”

Currently, the recommended daily intake of vitamin D in the United States is 200 international units (IU) for people up to 50 years old; 400 IU for people 51 to 70 years old; and 600 IU for people over 70 years old. Today there is a wide consensus among scientists that the relative daily intake of vitamin D should be increased to 2,000 to 4,000 IU for most adults.

“Worldwide public health is best served by a recommendation of higher daily intakes of vitamin D,” Norman said. “Currently, more than half the world’s population gets insufficient amounts of this vitamin. At present about half of elderly North Americans and Western Europeans and probably also of the rest of the world are not receiving enough vitamin D to maintain healthy bone.”

Reporting in a review paper in the July 28, 2010, issue of Experimental Biology and Medicine, Norman and Roger Bouillon of the Laboratory of Experimental Medicine and Endocrinology at the Katholieke Universiteit Leuven, Belgium, warn that if the current nutritional guidelines for vitamin D remain unchanged, rickets and osteomalacia, which could be easily prevented, will continue to occur.

They add that if the present guidelines for vitamin D intake are strictly implemented and applied worldwide to pregnant or lactating women, newborns and children, the occurrence of rickets in infants could be effectively eradicated.

Norman, the first author of the review paper, and Bouillon note that if the daily dietary intake of vitamin D is increased by 600-1000 IU in all adults above their present supply, it would bring beneficial effects on bone health in the elderly and on all major human diseases (e.g., cancer, cardiovascular, metabolic and immune diseases).

The researchers add, however, that if the vitamin D dietary intake were increased to 2000 IU per day and even more for subgroups of the world population with the poorest vitamin D status, it could favorably impact multiple sclerosis, type-1 diabetes, tuberculosis, metabolic syndrome, cardiovascular risk factors and most cancers.

About vitamin D:

Also known as the “sunshine vitamin,” vitamin D was discovered 90 years ago as a dietary agent that prevented the bone disease rickets.

Exposure to the sun is the body’s natural way of producing the vitamin. Skin exposed to solar UVB radiation can produce significant quantities of vitamin D. But this vitamin D synthesis is reliably available year-round only at latitudes between 40 degrees north and 40 degrees south. A combination of sunshine, food, supplements, and possibly even limited tanning exposure can raise the daily intake of the vitamin to 2000 IU.

Vitamin D is itself biologically inert. Its biological effects result only after it is metabolized first in the liver and then in the kidney — a process that converts the vitamin into a steroid hormone.

The best sources of unfortified foods naturally containing vitamin D are animal products and fatty fish and liver extracts like salmon or sardines and cod liver oil. Vitamin D-fortified food sources in the United States (the fortification levels aim at about 400 IU per day) include milk and milk products, orange juice, breakfast cereals and bars, grain products, pastas, infant formulas and margarines.

Vitamin D excess can cause health problems such as hypercalcemia, vomiting, thirst and tissue damage. The precise upper limit for daily vitamin D intake is not well defined.

ScienceDaily (Aug. 9, 2010)

Effectiveness of statins is called into question

The drugs clearly help patients who have already had a heart attack. But their use has skyrocketed in patients hoping to prevent a first heart attack. In those cases, the benefits are dubious.

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As the world’s most-prescribed class of medications, statins indisputably qualify for the commercial distinction of “blockbuster.” About 24 million Americans take the drugs – marketed under such commercial names as Pravachol, Mevacor, Lipitor, Zocor and Crestor – largely to stave off heart attacks and strokes.

At the zenith of their profitability, these medications raked in $26.2 billion a year for their manufacturers. The introduction in recent years of cheaper generic versions may have begun to cut into sales revenues for the brand-name drugs that came first to the market, but better prices have only fueled the medications’ use: In 2009, U.S. patients filled 201.4 million prescriptions for statins, according to IMS Health, which tracks prescription drug trends. That’s nearly double the number of prescriptions written for statins in 2001, four years after they arrived on the American pharmaceutical landscape.

But in recent months the drugs’ touted medical reputation has come under tough scrutiny.

Statins were initially approved by the Food and Drug Administration for the prevention of repeat heart attacks and strokes in patients with high cholesterol who had already had a heart attack. And used for that purpose – called “secondary prevention” – the drugs are powerful and effective medications, driving down patients’ risk of another heart attack or stroke by lowering their levels of LDL (or ‘bad’) cholesterol.

Then physicians came to believe statins could also reduce the risk of a first heart attack in people who have high LDL cholesterol but are nonetheless healthy. This use of statins – called “primary prevention” – has driven the growth in the market for statins over the last decade.

Today, a majority of people who use statins are doing so for primary prevention of heart attacks and strokes. It is this use of statins that has come under recent attack.

“There’s a conspiracy of false hope,” says Harvard Medical School’s Dr. John Abramson, who has cowritten several critiques of statins’ rise, including one published in June in the Archives of Internal Medicine. “The public wants an easy way to prevent heart disease, doctors want to reduce their patients’ risk of heart disease and drug companies want to maximize the number of people taking their pills to boost their sales and profits.”

The stakes of many

Heart patients and their physicians are not the only ones to pin their hopes on statins. The drug companies that brought statins to the market have explored the medications’ benefits in prevention or treatment of such conditions as Alzheimer’s disease, rheumatoid arthritis, prostate and breast cancer, kidney disease, macular degeneration and diabetic neuropathy. Although clear proof that statins could forestall or treat any of these diseases might bring in millions of new, paying customers, results have largely been mixed, inconclusive or disappointing.

In an ideal world, debate over the clinical virtues or vices of a drug would be long settled by the time the medication saw a meteoric rise in use. But in a healthcare system that relies on commercial incentives to spur drug development, prescription medications are a product like any other.

The FDA assesses drugs’ safety and effectiveness for specific use; but its judgments are based on preliminary data, most of it generated by a drug company seeking approval for its product. Once the agency approves a drug for marketing, the company that makes it will move quickly and aggressively to expand the universe of patients taking its product.

Sometimes, by the time the deliberate pace of medical research and debate suggests that a drug is not all it’s been cracked up to be, it’s already become a bestseller. Statins, say some who study the relationship between medicine and the drug industry, seem to fit that pattern.

Statins appear to drive down the risk of heart attack or stroke by lowering the levels of fatty deposits circulating in the bloodstream. Research suggests that the drugs dampen inflammatory processes that can prompt deposits of plaque to break away from blood vessel walls and cause sudden blockages of arteries leading to the heart or brain.

And yet, the relationship between cholesterol-lowering and heart disease is not perfectly understood, and the precise role of inflammation in heart disease is also uncertain.

Statins certainly decrease rates of heart attack in people who have clear signs of cardiovascular disease, but it’s not so clear they work that way in people who are healthy. In spite of that uncertainty, statins’ use for primary prevention has skyrocketed.

Behind the numbers

That’s the issue in the latest round of debate, which spilled onto the pages of the Archives of Internal Medicine in late June: whether statins prevent, safely and at a reasonable cost, the development of cardiovascular disease in people who are still healthy but are considered to be at high risk of a heart attack or stroke.

In the first of three studies published in the Archives last month, medical researchers found that, contrary to widely held belief, statins do not drive down death rates among those who take them to prevent a first heart attack. A second article cast significant doubt on the influential findings of a 2006 study, called JUPITER, that has driven the expansion of statins’ use by healthy people with elevated blood levels of C-reactive protein, a measure of inflammation. A third article suggested potential ethical, clinical and financial conflicts of interest at work in the execution of the JUPITER study and concluded the widely hailed trial was “flawed” and raises “troubling questions concerning the role of commercial sponsors.”

“Tens of billions of dollars of revenue for the sponsor over the patent life of the drug were at stake in the JUPITER trial, as well as potentially millions of dollars in royalties for the principal investigator,” wrote Dr. Lee Green of the University of Michigan Medical School in an editorial accompanying the trio of studies. “Doubtless, both sponsor and investigative team believe they made their design decisions for the right reasons,” Green added. “But social psychology research provides abundant evidence that we human beings both respond strongly to self-interest incentives and firmly believe that we do not.”

Statins still have ardent admirers, including cardiologist Steven Nissen of the Cleveland Clinic in Ohio. For many patients on a clear collision course with heart disease but not there yet, he said, statins make a difference. And even though recent studies question whether statins reduce heart attack deaths, Nissen added, many patients’ lives are clearly improved by pushing a heart attack further into the future.

The stakes of this debate are big and continuing to grow (see related story, “Pinning down the side effects of statins“). As many as three-quarters of patients currently taking statins haven’t yet had a stroke or heart attack; they have diabetes or high LDL cholesterol, conditions widely thought to put them at high risk of having one.

Those patients largely joined the ranks of statin consumers after 2001, when the National Heart, Blood and Lung Institute adopted guidelines on the treatment of patients with high cholesterol. The guidelines, updated again in 2004, suggested that as many as 36 million Americans should take statins – essentially tripling overnight the potential American market for the drugs. Of the nine experts involved in drafting the cholesterol treatment guidelines, the National Institutes of Health later acknowledged that eight had substantial financial ties to statin makers – links that may have predisposed them to view evidence of statins’ benefit in its most positive light.

Said Abramson, the author of “Overdosed America: The Broken Promise of American Medicine”: The best way to drive down the risk of developing cardiovascular disease in the first place is to exercise regularly, not smoke, drink in moderation and eat a healthy Mediterranean-style diet. But, he added, “this message gets drowned out by the commercial interests” of pharmaceutical companies who stand to benefit from increased sales.

melissa.healy@latimes.com

Copyright © 2010, Los Angeles Times

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